Heterocyclic derivatives

ABSTRACT

The present invention relates to a novel salt of enantiomer A of 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinoline carboxylic acid or a solvate thereof, to processes for its preparation, to pharmaceutical compositions containing it and to its use in therapy and in particularly its use as medicine for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.

CROSS REFERENCE TO RELATED APPLICATIONS

This application was filed pursuant to 35 U.S.C. §371 as a U.S. NationalPhase Application of International Application No. PCT/EP00/12335, filedDec. 7, 2000, which claims priority to Great Britain Priority PatentApplication Serial No. 9929037.1, filed Dec. 8, 1999.

The present invention relates to a novel salt of enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid or a solvate thereof, to processes for its preparation,to pharmaceutical compositions containing it and to its use in therapyand in particularly its use as medicine for antagonising the effects ofexcitatory amino acids upon the NMDA receptor complex.

The compound7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid of formula (I) is inter alia described in WO 99/64411 which alsorefers to physiologically acceptable salts thereof and more particularlyit describes an enantiomer of the compound of formula (I), which isreferred to therein as enantiomer A and a sodium salt thereof.

The enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid is a particularly potent antagonist of the NMDA receptor complex,and for its use in medicine there exists a need for the compound to beprepared in a form suitable for ease of isolation in a large scalemanufacture and for ease of formulating into an acceptable product foradministration to patients. These requirements are not conveniently metby either enantiomer A or sodium salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that the meglumine salt of enantiomer A can readily beprepared and isolated suitable in a pure form by a process that issuitable for use on a large scale, and the said salt can be convenientlyobtained with the required high degree of purity and good stability andthus fulfils the exacting criteria required in the preparation ofpharmaceutical compositions for administration to patients.

The present invention thus provides the meglumine salt of enantiomer Aof7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid of formula (I) or a solvate (e.g. hydrate) thereof (hereinafterreferred to as the compound of the invention).

Particularly the invention provides the meglumine salt of enantiomer Aof7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid in a crystalline form.

More particularly, according to one embodiment, the invention providesfor a hydrate crystalline form of the the meglumine salt of enantiomer Aof7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid (hereinafter referred to as form 1), characterised by the followingX-ray powder diffraction pattern expressed as 2 Theta (θ) value

Angle 2 θ 4.356 18.641 22.993 11.263 18.725 23.681 11.659 20.546 25.04312.757 21.362 25.598 12.877 22.234 26.823 13.962 22.379 28.753 15.48222.801 17.242 22.921

According to a further embodiment of the invention there is provided foranother crystalline form of the meglumine salt of enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid (hereinafter referred to as form 2) characterised by the followingX-ray powder diffraction pattern expressed as 2 Theta (θ) value

Angle 2 θ 5.480 19.553 25.225 8.233 20.505 25.802 10.942 21.939 26.48415.299 22.787 27.524 16.424 23.154 27.865 16.658 23.381 28.547 19.11624.194 38.345

The compound of the invention can be obtained in more than onecrystalline form. It is to be understood that the invention includes allsuch forms or mixture thereof. The compound of the invention is anexcitatory amino acid antagonist. More particularly it is a potentantagonist at the strychnine insensitive glycine binding site associatedwith the NMDA receptor complex. As such it is a potent antagonist of theNMDA receptor complex. This compound is therefore useful in thetreatment or prevention of neurotoxic damage or neurodegenerativediseases. Thus the compound is useful for the treatment of neurotoxicinjury which follows cerebral stroke, thromboembolic stroke, hemorrhagicstroke, cerebral ischemia, cerebral vasospam, hypoglycemia, amnesia,hypoxia, anoxia, perinatal asphyxia cardiac arrest. The compound of theinvention is useful in the treatment of chronic neurodegenerativediseases such as: Huntingdon's disease, Alzheimer's senile dementia,amyotrophic lateral sclerosis, Glutaric Acidaemia type, multi-infarctdementia, status epilecticus, contusive injuries (e.g. spinal cordinjury and head injury), viral infection induced neurodegeration (e.g.AIDS, encephalopaties), Down syndrome, ocular neurodegeneration (e.gglaucoma), epilepsy, schizophrenia, depression, migraine, headachesincluding cluster headaches and or tension headaches, anxiety, pain (e.ginflammatory pain and neuropathic pain), neurogenic bladder, irritablebowel syndrome and or visceral hyperalgesia, emesis, irritative bladderdisturbances, drug dependency, including withdrawal symptoms fromalcohol, cocaine, opiates, nicotine (e.g. smoking cessation)benzodiazepines and inhibition of tolerance induced by opioids (i.e.morphine).

The potent and selective action of the compound of the invention at thestrychnine-insensitive glycine binding site present on the NMDA receptorcomplex may be readily determined using conventional test procedures.Thus the ability to bind at the strychnine insensitive glycine bindingsite was determined using the procedure of Kishimoto H et al., JNeurochem 1981, 37, 1015-1024. The selectivity of the action ofcompounds of the invention for the strychnine insensitive glycine sitewas confirmed in studies at other ionotropic known excitatory amino acidreceptors. Thus the compound of the invention was found to show littleor no affinity for the kainic acid (kainate) receptor,a-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptoror at the NMDA binding site.

The compound of the invention may be found to inhibit NMDA inducedconvulsions in mice using the procedure Chiamulera C et al.,Psychopharmacology (1990), 102, 551-552.

The neuroprotective activity of the compound of the invention may bedemonstrated in the middle cerebral artery occlusion preparation inmice, using the procedure described by Chiamulera C. et al., EuropeanJournal of Pharmacology, 216 (1992) pp. 335-336.

The ability of compound of the invention to alleviate withdrawalsymptoms from nicotine following smoking cessation may be demonstratedin conventional tests of nicotine induced relapse using the proceduredescribed in C. Chiamulera et al., Arch. Pharmacol., 358, 1998.

The ability of the compound of the invention to inhibit pain may bedemonstrated in conventional analgesic screen such as those described byDubuisson and Dennis, Pain, 1977, 4:161-174; J. J. Bennett and J. K Xue,Pain, 1988, 41, 87-107.

The invention also provides for the use of the compound of the inventionfor use in therapy and in particular use as medicine for antagonisingthe effects of excitatory amino acids upon the NMDA receptor complex.

The invention also provides for the use of the compound of the inventionfor the manufacture of a medicament for antagonising the effects ofexcitatory amino acids upon the NMDA receptor complex.

According to a further aspect, the invention also provides for a methodfor antagonising the effects of excitatory amino acids upon the NMDAreceptor complex, comprising administering to a patient in need thereofan antagonistic amount of the compound of the invention.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylactics as well as the treatment ofestablished diseases or symptoms.

It will further be appreciated that the amount of the compound of theinvention required for use in treatment will vary with the nature of thecondition being treated, the route of administration and the age and thecondition of the patient and will be ultimately at the discretion of theattendant physician. In general however doses employed for adult humantreatment will typically be in the range of 2 to 800 mg per day,dependent upon the route of administration.

Thus for parenteral administration a daily dose will typically be in therange 20-100 mg, preferably 60-80 mg per day. For oral administration adaily dose will typically be within the range 200-800 mg, e.g. 400-600mg per day.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example as two,three, four or more sub-doses per day.

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.

The invention thus further provides a pharmaceutical formulationcomprising the compound of the invention together with one or morepharmaceutically acceptable carriers thereof and, optionally, othertherapeutic and/or prophylactic ingredients. The carrier(s) must be‘acceptable’ in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The compositions of the invention include those in a form especiallyformulated for oral, buccal, parenteral, inhalation or insufflation,implant or rectal administration.

Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, for example, syrup, acacia, gelatin,sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone;fillers, for example, lactose, sugar, microcrystalline cellulose,maize-starch, calcium phosphate or sorbitol; lubricants, for example,magnesium stearate, stearic acid, talc, polyethylene glycol or silica;disintegrants, for example, potato starch or sodium starch glycollate,or wetting agents such as sodium lauryl sulphate. The tablets may becoated according to methods well known in the art. Oral liquidpreparations may be in the form of, for example, aqueous or oilysuspensions, solutions emulsions, syrups or elixirs, or may be presentedas a dry product for constitution with water or other suitable vehiclebefore use. Such liquid preparations may contain conventional additivessuch as suspending agents, for example, sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats; emulsifying agents, for example, lecithin, sorbitan mono-oleate oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters, propyleneglycol or ethyl alcohol; solubilizers such as surfactants for examplepolysorbates or other agents such as cyclodextrins; and preservatives,for example, methyl or propyl p-hydroxybenzoates or ascorbic acid. Thecompositions may also be formulated as suppositories, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The composition according to the invention may be formulated forparenteral administration by injection or continuous infusion.Formulations for injection may be presented in unit dose form inampoules, or in multi-dose containers with an added preservative. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilising and/or dispersing agents. Alternatively theactive ingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile, pyrogen-free water, before use.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurised packs, with the use of a suitablepropellant, such as dichlorodifluoromethane, trichlorofluoromethane,dichloro-tetrafluoroethane, carbon dioxide or other suitablepropellants, such as dichlorodifluoromethane, trichlorofluoromethane,dichloro-tetrafluoroethane, carbon dioxide or other suitable gases, orfrom a nebuliser. In the case of a pressurised aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablecarrier such as lactose or starch. The powder composition may bepresented in unit dosage form in, for example, capsules or cartridges ofe.g. gelatin, or blister packs from which the powder may be administeredwith the aid of an inhaler or insufflator.

The composition according to the invention may also be formulated as adepot preparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

The compositions according to the invention may contain between 0.1-99%of the active ingredient, conveniently from 30-95% for tablets andcapsules and 3-50% for liquid preparations.

A further aspect of the invention provides a process for the preparationof the compound of the invention.

Thus in one embodiment compound of the invention may be prepared bytreating a solution of the enantiomer A (I) with meglumine in a suitablesolvent such as aprotic solvent (i.e. actetone, tetrahydrofuran) oralkanol such as ethanol.

The invention further provides a method for producing the compound ofthe invention in a crystalline form.

Thus the compound of the invention in hydrate crystalline form (form 1)may be prepared by treating a solution of enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid in ethanol with meglumine dissolved in water. The reaction iscarried out at room temperature and in an environment free of thecompound of the invention in crystalline form 2.

The crystalline form 2 may obtained by crystallisation of the compoundof the invention from a mixture of water and a water miscible organicantisolvent. Suitable water miscible organic antisolvents for use in thecrystallisation include alkanol (e.g. ethanol, IMS (ethanol/methanol95/5) or isopropanol), acetone or acetonitrile. A particularlyconvenient water miscible organic antisolvent is ethanol or acetone.

Conveniently the crystallisation process is carried out by adding theantisolvent to a solution of the compound of the invention dissolved inwater.

In a further embodiment of the process, the crystalline form 2 may beobtained by crystallisation of the compound of the invention from amixture of suitable organic solvents. Thus, form 2 may be obtained bydissolution of the compound of the invention in a suitable organicsolvent (i.e. N,N-dimethylformamide or 1-methyl-2-pyrrolidone) followedby treatment with a suitable organic antisolvent such as alkanol (e.g.ethanol, IMS (ethanol/methanol 95/5) or isopropanol) or an aproticsolvent (e.g. acetone, tetrahydrofuran dichloromethane, ethylacetate,toluene, or acetonitrile). The process is preferably carried out at atemperature ranging between 20-45° C.

The enantiomer A of the compound of formula (I) may be preparedaccording to the processes described in WO 99/64411 which isincorporated by reference. In a preferred embodiment, the enantiomer Aof the compound of formula (I) may be prepared by stereoselectiveenzymatic hydrolysis of compounds of formula (II) with ferulic acidesterase in a pure form.

wherein R is a carboxyl protecting group.

Suitable carboxyl protecting group R for use in this reaction includesC₁₋₄ alkyl such as methyl, ethyl, propyl, butyl or arylmethyl groupssuch as benzyl, nitrobenzyl or trityl.

The reaction is conveniently carried out in an aprotic solvent such asDMSO, tetrahydrofuran in the presence of a suitable aqueous buffer (i.e.citrate, phosphate buffer or CaCl2). If required, a solubilising agentsuch as Tween-80 may be added to the reaction mixture.

In a further process the enzyme may be immobilized and the reaction iscarried out in essentially “neat” water-saturated organic solvents suchas methyl tert-butyl ether or tert-amyl alcohol.

The stereoselective enzymatic hydrolysis of compounds of formula (II)with ferulic acid esterase in a pure form is novel and represents afurther aspect of the invention.

The invention also extends to the meglumine salt of enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid of formula (I) or a solvate thereof when prepared from theenantiomer A of formula (I) which has been obtained by stereoselectiveenzymatic hydrolysis of compounds of formula (II) with ferulic acidesterase in a pure form.

Meglumine is commercially available (Aldrich).

In the Intermediates and Example unless otherwise stated: Melting points(m.p.) were determined on a Gallenkamp m.p. apparatus and areuncorrected. All temperatures refer to ° C. Proton Magnetic Resonance(¹H-NMR) spectra were recorded at 500 MHz, chemical shifts are reportedin ppm downfield (d) from Me₄Si, used as internal standard, and areassigned as singlets (s), doublets (d), doublets of doublets (dd),triplets (t), quartets (q) or multiplets (m). Column chromathography wascarried out over silica gel (Merck AG Darmstaadt, Germany).DBU=1,8-diazobicyclo [5,4,0]undec-7-ene.

The X-ray powder diffraction pattern of a crystalline form of thecompound of the invention was obtained by loading the sample into thediffractometer (Siemens D5005 X-ray diffractometer equipped with θ/θgoniometer, scintillation counter and graphite monochromator. Thediffractometer was set up with the instrumental parameters given below:

Instrumental Parameters

MONOCHROMATIC RADIATION: Cu-1.54056/1.54439

2θ RANGE: 20-40° 2θ

GENERATOR VOLTAGE/CURRENT: 40 kV/50 mA

STEP SIZE: 0.02° 2θ

TIME PER STEP: 2 sec⁻¹

ROTATION: on

DIVERGENCE/ANTISCATTERING SLIT: variable

SAMPLE HOLDER: round cavity on low-background plate.

The spectrum obtained was analysed using the data evaluation softwareEVA3.0.

Enantiomer A refers to a single enantiomer whose absolute stereochemistry was not determined

INTERMEDIATE 1 (±)-Ethyl 2-(5-chloro-2-iodoanilino)-4-pentenoate

To a solution of 2-iodo 4 chloro aniline (9.1 g) in dry toluene (150 ml)ethyl glyoxylate (50% solution in toluene, 14.6 ml) and MgSO₄ (2 g) wereadded and the resulting suspension was refluxed overnight. It was thenfiltered and concentrated to dryness under high vacuum at 50° C. for 1.5h. The resulting brown oil was dissolved in dichloromethane (150 ml)cooled to −78° C. and TiCl₄ (99.995% purity, 4 ml) was added viasyringe. The suspension was stirred 15 min at −78° C., then allowed towarm to rt over 15 min before being cooled again to −78° C.Allyltributyltin (17 ml) was then added and the reaction allowed toproceed for 1 h. The black solution was poured into 200 ml of ethylacetate and washed first with a saturated solution of NH₄Cl (2×150 ml),then with water and brine. The organic phase was dried and concentratedto give the crude product, which was purified by column chromatography(cyclohexane, then cyclohexane/ethyl acetate 98/2) to give the titlecompound (10.4 g) as a colourless oil.

NMR (CDCl₃) δ (ppm) 7.57 (d, 1H), 6.49 (dd, 1H), 6.45 (dd, 1H), 5.79 (m,1H), 5.25 (dd, 1H) 5.24 (dd, 1H), 4.83 (d, 1H), 4.25 (q,2H), 4.13 (m,1H), 2.66 (m, 2H), 1.30 (t, 3H)

INTERMEDIATE 2 (±)-Ethyl 2-(5-chloro-2-iodoanilino)-4-oxobutanoate

A solution of intermediate 1 (5.2 g) in dichloromethane (150 ml) wascooled to −78° C. and ozone was bubbled through it until the clearsolution became brick-red. At this point the flux of ozone wasinterrupted and the solution was purged with nitrogen for a few minutes.Triphenyl phosphine (7.1 g) was added and stirring continued for 1.5 h,without control of the temperature. The resulting solution was pouredinto 200 ml of ethyl acetate and washed first with a saturated solutionof NH₄Cl (2×150 ml), then with water and brine. The organic phase wasdried and concentrated to give the crude product, which was purified bycolumn chromatography (cyclohexane/ethyl acetate 80/20) to give thetitle compound (2.4 g) as a colourless oil. ¹NMR (DMSO) δ (ppm) 9.80 (t,1H), 7.57 (d, 1H), 6.55 (d, 1H), 6.51 (dd, 1H), 4.99 (d, 1H), 4.46 (m,1H), 4.24 (q, 2H), 3.08 (m, 2H), 1.28 (t, 3H)

INTERMEDIATE 3 (±) E-Ethyl2-(5-chloro-2-iodoanilino-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)butanoate (3a);(±)-Z-Ethyl2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)butanoate(3b)

To a solution of intermediate 2 (2.4 g) in acetonitrile (100 ml) at r.t.Tributyl (2-oxo-1-phenylpyrrolidin-1-yl)phosphonium bromide (3.7 g) andDBU (13 ml) were added and stirring was continued overnight at −20° C.The crude solution was poured into 200 ml of ethyl acetate and washedwith a saturated solution of NH₄Cl (2×150 ml), then with water andbrine. The organic phase was dried and concentrated to give the crudeproduct as a 4/1 mixture of 3a/3b compounds. Purification by columnchromatography (cyclohexane/ethyl acetate 80/20) gave the title 3a (2.16g) and the 3b (0.5 g) compounds as colourless oils.

INTERMEDIATE 3a

¹NMR (CDCl₃) δ (ppm) 7.72 (d, 2H), 7.56 (d, 1H), 7.38 (t, 2H), 7.16 (t,1H), 6.6 (m, 1H), 6.50 (dd, 1H), 6.49 (d, 1H), 4.88 (d, 1H), 4.26 (m,3H), 3.87 (t, 2H), 2.79 (m, 4H), 1.30 (t, 3H)

INTERMEDIATE 3b

¹NMR (CDCl₃) δ (ppm) 7.69 (d, 2H), 7.52 (d, 1H), 7.38 (t, 2H), 7.17 (t,1H), 6.47 (d, 1H), 6.44 (dd, 1H), 5.98 (m, 1H), 5.00 (d, 1H), 4.22 (m,2H), 4.13 (m, 1H), 3.84 (t, 2H), 3.2-3.6 (m, 2H), 2.85 (m, 2H), 1.26 (t,3H)

INTERMEDIATE 4 (±)-Ethyl7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate

To a solution of intermediate 3b (370 g) in toluene (5.2 lit),Triethylamine (248 ml), Triphenylphosphine (7.4 g) and PdCl₂ (2.52 g)were added. The resulting solution was warmed to 100° C. and stirred for2 h. The suspension was chilled to 20-25° C. and toluene (2.6 ml) wasadded.

The reaction mixture was washed with NH₄Cl 8% (3×5.2 lit) and water (5.2lit). The organic layer was filtered over a celite pad and it was washedwith toluene (1 lit); then it was distilled under vacuum (T=50° C.; P=60mbar) to reach 6.3 lit. After cooling to T=20-25° C., isooctane (5.2lit) was dropped over 30 min. The precipitate was stirred for 2 h 30 minthen it was filtered and washed with a mixture toluene/isooctane 1/1(1.85 lit). The yellow solid was dried in vacuum at T=40° C. for 18 h toobtain the title compound as a yellow solid (210 g).

m.p. 160-162° C.

¹NMR (DMSO): 7.72 (m, 2H); 7.39 (m, 2H); 7.20 (d, 2H); 7.15 (m, 2H);6.96 (dd, 1H); 6.74 (d, 1H); 6.57 (dd, 1H); 4.29 (dd, 1H); 4.21 (m, 1H);4.02 (m, 1H); 3.93 (m, 1H); 3.82 (m, 1H); 3.69 (m, 1H); 3.20 (m, 1H).2.92 (m, 2H); 2.92 (m, 2H); 0.93 (t, 3H).

EXAMPLE 1 (−)Meglumine salt of enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicAcid (Form 2)

Method A

16.5 g of Lipase Amano AP12 (Aspergillus niger lipase) were suspended in360 ml of 0.1M citrate buffer (pH=3) in a stirred vessel at 15° C. 27.5g of intermediate 4 were dissolved in 190 ml of dimethyl sulphoxide at20° C. and this solution added into the vessel under vigorous stirring.The mixture was stirred at 37° C. for 24 hrs and 27.5 g of filter aid(Dicalite) were added to the reaction mixture which was then cooled to20° C. After addition of 275 ml of aq. 0.2M hydrochloric acid themixture was cooled to +6° C. and then filtered. The filter cake waswashed with 140 ml of aq. 0.2M hydrochloric acid and 140 ml of waterbefore being dried. The so obtained dried filter cake (55 g) wasextracted at 20° C. with 660 ml of acetone, then filtered off washingwith 220 ml of acetone. To the filtrate, 33 ml of an aqueous solution ofmeglumine (0.2 g/ml) were added. The so obtained suspension was digestedand the solid filtered and washed with 275 ml of acetone. After dryingthe crude title compound was obtained as a yellow solid (16.2 g). 4 g ofthis crude compound were then dissolved in 10 ml of water by heating at50° C., then 110 ml of EtOH were added. After digestion at 20° C. thesolid was filtered and dried to obtain the purified title compound as ayellow solid (3.75 g), m.p. 186° C.

The title compound (5 mg) was dissolved in 1 ml of a mixture D₂O/DMSO95/5.

¹H-NMR (D₂O/DMSO 95/5) δ (ppm) 7.44 (2H, d), 7.37 (2H, t), 7.19 (1H, t),7.16 (1H, d), 6.66 (1H, d), 6.58 (1H, dd), 3.96 (1H, m), 3.78-3.50 (8H,m), 3.46 (1H, dd), 3.99 (1H, dd), 3.10 (1H, dd), 3.05 (1H, d), 3.02 (2H,m), 2.64 (3H, s).

[α]_(D)=−321.7; λ=598 nm; 20° C. conc mg/ml 0.12% solvent=methanol.

Method B

To a warmed at 35° C. 0.1M Sodium citrate buffer obtained by mixing a0.1M aqueous solution (412 ml) of citric acid and a 0.1M aqueoussolution (196 ml) of trisodic citrate dihydrate into a jacketed reactor,an aqueous solution (Conc=40 mg/ml) of the enzyme ferulic acid esterase(19.6 ml) and dimethyl sulfoxide (98 ml) were added. To the resultingsolution, a solution of Intermediate 4 (49 g) in dimethyl sulfoxide (270ml) was added. Then the mixture was stirred at 37-38° C. for 24 hrs.

After cooling at 20° C. the reaction mixture was extracted twice with2-butanone (1470 mL) and the organic layer was washed with a 6% sodiumchloride aqueous solution (2×980 ml) and a 25% sodium chloride aqueoussolution (392 ml) then, after addition of further 2-butanone (490 ml)the solvent was distilled off at atmospheric pressure to a residual 200ml volume. Then acetone (1323 ml) was added to the mixture and a 20%aqueous meglumine solution (60 ml) was dropped into the mixture. Theresulting suspension was stirred for 1 h, then filtered, washed withacetone (490 ml) and dried at 40° C. under vacuum for ca 16 hrs toobtain the crude title compound as a yellow solid (26.9 g).

26.8 g of the crude title compound was dissolved with water (107, 2 ml)at 55° C. and after filtration cooled at 45° C. Then acetone (268 ml)was dropped under stirring and the mixture seeded with the titlecompound. Acetone (402 ml) was then further added and the resultingslurry was stirred at 20° C. for 1 hr and at 2° C. for 2 hrs and thensolid was filtered washed with acetone (134 ml) and dried under vacuumat 40° C. for ca 16 hrs to obtain the title compound (23 g), m.p.185-187° C.

TABLE 1 The X-ray powder diffraction pattern of the product of Example 1in terms of ‘d’ spacings is as follows Angle (°2θ) d value (A) 5.48016.114 8.233 10.731 10.942 8.079 15.299 5.787 16.424 5.393 16.658 5.31719.116 4.639 19.553 4.536 20.505 4.328 21.939 4.048 22.787 3.899 23.1543.838 23.381 3.801 24.194 3.676 25.225 3.528 25.802 3.450 26.484 3.36327.524 3.238 27.865 3.199 28.547 3.124 38.345 2.346

EXAMPLE 2 (−)Meglumine salt of enantiomer A of7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicAcid (Form 1)

(−)-Sodium7-chloro4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate(2.5g) was suspended in ethyl acetate (75 ml) and extracted with aqueous HCl1.5N (25 ml). The organic layer was evaporated to dryness to obtain7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinoline-2-carboxylicacid_as a white foam (2.3 g) which was dissolved in ethanol (69 ml) at23° C. under nitrogen and then a solution of meglumine (1.25 g) in water(5.3) was added in 20 minutes. The suspension was stirred at 23° C.under nitrogen for 24 hours. The solid was filtered and dried at 40° C.for 20 hours (3.0 g), m.p. 112° C.

¹H-NMR (D₂O/DMSO 95/5) δ (ppm) 7.73 (2H, d), 7.38 (2H, t), 7.15 (1H, d),7.13 (1H, t), 6.77 (1H, d), 6.45 (1H, dd), 6.40 (1H, bs), 4.10 (1H, bm),3.79 (3H, m), 3.64 (1H, dd), 3.60 (1H, bm), 3.55 (1H, dd), 3.47 (1H, m),3.40 (1H, d). 3.38 (1H, t), 3.16 (1H, m), 2.98 (1H, m), 2.85 (1H, m),2.78 (1H, m), 2.70 (1H, bm), 2.42 (3H, s).

X ray powder diffraction data are reported in Table 2.

TABLE 2 The X-ray powder diffraction pattern of the product of Example 2in terms of ‘d’ spacings is as follows Angle (°2θ) d value (A) 4.35620.270 11.263 7.849 11.659 7.584 12.757 6.934 12.877 6.869 13.962 6.33715.482 5.719 17.242 5.139 18.641 4.756 18.725 4.735 20.546 4.319 21.3624.156 22.234 3.995 22.379 3.969 22.801 3.897 22.921 3.877 22.993 3.86523.681 3.754 25.043 3.553 25.598 3.477 26.823 3.321 28.753 3.102

PHARMACY EXAMPLES

A. Capsules/Tablets Active ingredient 20.0 mg Starch 1500 32.5 mgMicrocrystalline 200.0 mg Cellulose Croscarmellose Sodium 6.0 mgMagnesium Stearate 1.5 mg

The active ingredient is blended with the other excipients. The blendcan be used to fill gelatin capsules or compressed to form tablets usingappropriate punches. The tablets can be coated using conventionaltechniques and coatings.

B. Tablets Active ingredient 20.0 mg Sorbitol 200.0 mg Microcrystalline70.0 mg Cellulose Povidone 25.0 mg Croscarmellose 6.0 mg SodiumMagnesium Stearate 1.5 mg

The active ingredient is blended with lactose, microcrystallinecellulose and part of the croscarmellose sodium. The blend is granulatedwith povidone after dispersing in a suitable solvent (i.e. water). Thegranule, after drying and comminution is blended with the remainingexcipients. The blend can be compressed using appropriate punches andthe tablets coated using conventional techniques and coatings.

C. Bolus Active ingredient 0.1-32 mg/ml Trometamol 1.0-5.0 mg/ml waterfor injection qs to 1 ml

The formulation may be packed in glass ampoules or vials and syringeswith a rubber stopper and a plastic/metal overseal (vials only).

D. Infusion Active ingredient 0.01-3.2 mg/ml Trometamol 0.2-1.0 mg/ml 5%dextrose injection qs to 100 ml

The formulation may be packed in glass vials or plastic bags.

No untoward effects have been observed when compound of the inventionhas been administred to mice at the pharmacological active doses.

What is claimed is:
 1. (−) Meglumine salt of 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid.
 2. A crystalline form of the compound as claimed in claim
 1. 3. A process for the preparation of a crystalline form as claimed in claim 2 which comprises crystallising the meglumine salt from a mixture of water and a water miscible organic solvent or from a mixture of suitable organic solvents.
 4. A pharmaceutical composition comprising a compound as claimed in claim 1 in admixture with one or more physiologically acceptable carriers or excipients.
 5. A method of treatment of a mammal for conditions where antagonising the effects of excitatory amino acids on the NMDA receptor complex is of therapeutic benefit, comprising administration of an effective amount of a compound as claimed in claim
 1. 6. The method according to claim 5, wherein said mammal is man.
 7. A method for selectively antagonising the strychnine insensitive glycine binding site associated with the NMDA receptor complex, said method comprising administration of a compound according to claim
 1. 8. A method for the treatment or prophylaxis of neurotoxic damage or neurodegenerative diseases where antagonising the NMDA receptor complex is of therapeutic benefit, in a mammal, said method comprising administrator of an effective amount of a compound according to claim
 1. 9. The method according to claim 8, wherein said mammal is man.
 10. A method for the treatment or prophylaxis of migraine in a mammal, said method comprising administration of an effective amount of a compound according to claim
 1. 11. The method according to claim 10, wherein said mammal is man.
 12. A method for the treatment or prophylaxis of withdrawal symptoms from nicotine in a mammal, said method comprising administration of an effective amount of a compound according to claim
 1. 13. The method according to claim 12, wherein said mammal is man.
 14. A method for the treatment or phophylaxis of withdrawal symptoms from alcohol in a mammal, said method comprising administration of an effective amount of a compound according to claim
 1. 15. The method according to claim 14, wherein said mammal is man.
 16. A method for the treatment or prophylaxis of pain in a mammal, said method comprising administration of an effective amount of a compound according to claim
 1. 17. The method according to claim 16, wherein said mammal is man.
 18. A method for the treatment or prophylaxis of inflammatory pain in a mammal, said method comprising administration of an effective amount of a compound according to claim
 1. 19. The method according to claim 18, wherein said mammal is man.
 20. A method for the treatment or prophylaxis of neuropathic pain in a mammal, said method comprising administration of an effective amount of a compound according to claim
 1. 21. The method according to claim 20, wherein said mammal is man.
 22. A crystalline form of a compound according to claim 1 having the X-ray powder diffraction pattern expressed in terms of angles 2θ and d spacings as follows: Angle (°2θ) d value (A) 5.480 16.114 8.233 10.731 10.942 8.079 15.299 5.787 16.424 5.393 16.658 5.317 19.116 4.639 19.553 4.536 20.505 4.328 21.939 4.048 22.787 3.899 23.154 3.838 23.381 3.801 24.194 3.676 25.225 3.528 25.802 3.450 26.484 3.363 27.524 3.238 27.865 3.199 28.547 3.124 38.345 2.346 